Reaction of a nitrile with ammonia or an amine leads to the formation of an amidine. In the simplest case, reaction, for example, of acetonitrile with ammonia yields acetamidine, ##STR1## the analogue of acetic acid in the liquid ammonia solvent system. Reaction of cyanamide H.sub.2 NCN with an amine RNH.sub.2 yields an aminoamidine or guanidine ##STR2## Reaction of an amine (RNH.sub.2) with potassium isothiocyanate yields a mercapto-amidine, more commonly known as an isothiourea, ##STR3## which structure can tautomerize to a thiourea, ##STR4##
Ethenediamines of the formula, ##STR5## can also be looked upon as substituted amidines, since a tautomer of the above formula would have the following structure ##STR6##
All of the above substituted amidines--thioureas, guanidines, and ethenediamines--form part of the chemical structure of a new group of histamine H.sub.2 -receptor antagonists useful in treatment of peptic ulcer.
One of the first chemical compounds to be recognized as a powerful H.sub.2 -receptor antagonist useful in the treatment of peptic ulcer was a thiourea, burimamide, N-methyl-N'-(4-[4(5)-imidazolyl)]butyl)thiourea, having the following formula: ##STR7## The properties of this compound are disclosed in the Pharmacological Basis of Therapeutics, Goodman & Gilman 5th Ed. (MacMillan Publishing Co., Inc., New York) page 612.
A second generation of histamine H.sub.2 -receptor atagonists involved compounds developed by Black, Durant and co-workers with a structure more or less similar to the above but in which there was a permissible interrupting group--oxygen, sulfur or NH--in the alkyl side chain attached to the hetero ring. The most prominent of these compounds has been cimetidine, chemically N-cyano-N'-methyl-N"-[2-([(5-methyl-1H-imidazol-4-yl)methyl]thio)ethyl]gua nidine represented by formula II below: ##STR8##
A large number of patents based upon four original filings (Ser. Nos. 230,451; 284,992, 384,993; and 385,027) have issued to Durant et al including the following issued U.S. Pat. Nos. 3,950,333; 4,049,672; 4,022,797; 4,137,237; 4,024,271; 4,070,475; 4,154,844; 3,905,984; 4,027,026; 3,932,427; 4,018,928; 3,950,353; 4,053,473; 4,018,931; 4,069,327; 4,151,288; 4,000,296; 4,083,988; 4,129,657; 4,098,898; 4,166,856; 4,072,748; 3,971,786; 4,060,620; 3,876,647; 3,920,822; 3,897,444; and 3,975,530.
Other disclosed ring systems in addition to imidazole include pyrazole, pyridine, pyrimidine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole and tetrahydroimidazo[1,5-a]pyridine, with the greatest emphasis being placed on compounds having an imidazole ring system. Groupings which may be present at the terminal end of the alkyl or alkylthioalkyl bridging group include guanidine, cyanoguanidine, urea, ethenediamine and thiourea.
The above list of numbered patents to Durant and co-workers is not exhaustive since several patents may have issued as divisions of a single parent. Each of these divisions has, of course, an identical disclosure to its parent and it is believed that the above list is a fair representation of the Durant et. al., patents.
Patents referring to thiazole or oxazole ring systems are of particular relevance to this invention. The two basic disclosures by the Durant groups are contained in U.S. Pat. No. 3,950,333 and U.S. Pat. No. 3,950,353; both of these are continuations-in-part of Ser. No. 290,584 which was in turn a continuation-in-part of Ser. No. 230,451. In U.S. Pat. No. 3,950,333, the disclosure relating to thiazoles begins at Example 115, column 37. Thiazoles substituted with a chloro or an alkyl group are described. The thiazole nucleus is then attached at the 2- or 4-position of the thiazole ring to an alkylthioalkyl side chain terminating in an N-cyano-N'-methylguanidine. This disclosure is followed by similar disclosures for isothiazoles, oxazoles and isoxazoles. The disclosure in U.S. Pat. No. 3,950,353 relating to thiazoles begins at Example 110, column 37. Here, substantially the same thiazole nucleus is attached to an N-methylthiourea. A similar disclosure is present for isothiazoles, oxazoles and isoxazoles. U.S. Pat. No. 4,022,797, a division, specifically claims the cyanoguanidine derivatives and U.S. Pat. No. 4,137,234, another division, specifically claims thioureas.
U.S. Pat. No. 4,000,296 discloses and claims a group of N-alkyl or N-arylsulfonyl-N'-alkyl-N"(heterocyclealkylthioalkyl)guanidines in which the heterocycle can be thiazole, isothiazole, oxazole or isoxazole. Alkyl, alkylaminoalkyl and alkyloxyalkyl bridging groups (connecting the heterocyclic to the substituent amidine group) are also disclosed. Substituted heterocycles belonging to any of the above classes are not disclosed. U.S. Pat. No. 4,166,856, originating with the Durant group, discloses and claims a number of imidazoles and thiazoles carrying the usual alkylthioalkyl-guanidine, -thiourea or -ethenediamine side chain, which is invaribly in the 2-position of the ring. The N'-nitrogen can be substituted with groups other than alkyl including allyl, phenylethyl, 2,2,2-trifluoroethyl, etc. The thiazole ring may also be substituted by alkyl, hydroxy, halogen or amino.
Another group of investigators under Yellin has disclosed--see U.S. Pat. Nos. 4,165,377 and 4,165,378--certain novel thiazoles having a side chain such as that discussed above attached at the 4-position of the thiazole ring; i.e., an alkylthioalkyl-guanidine, -ethenediamine or -thiourea group attached thereto but also bearing a guanidino group in the 2-position. Alkylene, alkenylene and alkyloxyalkyl bridging groups are also disclosed. A representative compound is 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole which is said to have greatly increased activity over cimetidine.
A third research group at Allen and Hanbury Ltd. has prepared compounds with a furan ring carrying the standard alkylthioalkyl (or alkyloxyalkyl or alkyl) side chain terminating in a substituted guanidine or ethenediamine group, and also having a dialkylaminoalkyl substituent attached at a second position in the furan ring--see U.S. Pat. Nos. 4,128,658 and 4,168,855. Belgian Pat. Nos. 867,105 and 867,106 disclose the corresponding thiophene and aminoalkylbenzenes. Several of the compounds thus produced had a greater activity than cimetidine.
Finally, a research group at Bristol-Myers have issued two United States patents involving different heterocycles. The first of these, U.S. Pat. No. 4,203,909, relates to furans carrying an alkylthioalkyl-guanidine (or thiourea or ethenediamine) side chain in the 2-position and an aminoalkyl side chain in the 5-position. However, it is a requirement of these structures that the N'-nitrogen carry only an alkynyl group. One of the compounds, 1-nitro-2-(2-propynylamino)-2-(2-[(5-dimethylaminomethyl-2-furyl)methylthi o]ethylamino)ethylene, is said to have 7.45 times the activity of cimetidine in a standard H.sub.2 receptor assay. The second patent, U.S. Pat. No. 4,200,578, covers broadly thiazoles substituted with an alkylthioalkylguanidine (or thiourea or ethenediamine) side chain, but again carrying an obligatory alkynyl group on the N'-nitrogen. Other permissible substituents in the thiazole ring include alkyl, guanidino or aminoalkyl. Despite the broad disclosure, the actual working examples are limited to thiazoles carrying the alkylthioalkylguanidine, etc. side chain in the 2-position of the thiazole ring except for a few compounds in which the side chain is carried in the 4 -position, and there is an obligatory guanidino group in the 2-position. Synthetic Schemes I through VIII of the patent are suitable only for preparing 2-substituted thiazoles. Example 22 discloses thiazoles substituted in the 4-position but these thiazoles either do not carry a second ring substituent or, if there is one, it is a guanidino group in the 2-position. In the H.sub.2 receptor assay, the most active compounds disclosed had an activity less than twice that of cimetidine.
To summarize, thiazoles in which there is a 4-alkylthioalkyl(or alkyl)-guanidine (or thiourea or ethenediamine) side chain are known wherein the thiazole group can be substituted in the 2- or 5-position with guanidino, methyl, chloro and aminoalkyl. The disclosure relating to thiazoles substituted with an aminoalkyl group at one position in the thiazole ring and, at a second position, a bridging alkylthioalkyl, alkylene, alkenylene or alkyloxyalkyl group terminating in a substituted amidine group, is restricted to amidines carrying a N-alkynyl group as part of the terminal grouping.